CD3 has been known for many years and therefore has been subject of interest in many aspects. Specifically antibodies raised against CD3 or the T-cell Receptor Complex, which CD3 is part of, are known. An in vitro characterization of five humanized OKT3 effector function variant antibodies has been described (Xu et al., 2000, Cell Immunol. 200(1):16-26).
Treatment with the anti-CD3 monoclonal antibody hOKT3gamma1(Ala-Ala) results in improved C-peptide responses and clinical parameters for at least 2 years after onset of type 1 diabetes in absence of continued immunosuppressive medications (Herold et al., 2005, Diabetes, 54(6):1763-9).
CD3 antibodies cross-reactive to cynomolgus and/or rhesus monkey CD3 have been described (WO2012162067, WO2008119567).
A promising approach to improve targeted antibody therapy is by delivering cytotoxic cells specifically to the antigen-expressing cancer cells. This concept of using T-cells for efficient killing of tumor cells has been described in Staerz, et. al., 1985, Nature 314:628-631). However, initial clinical studies were rather disappointing mainly due to low efficacy, severe adverse effects (cytokine storm) and immunogenicity of the bispecific antibodies (Muller and Kontermann, 2010, BioDrugs 24: 89-98). Advances in the design and application of bispecific antibodies have partially overcome the initial barrier of cytokine storm and improved clinical effectiveness without dose-limiting toxicities (Garber, 2014, Nat. Rev. Drug Discov. 13: 799-801; Lum and Thakur, 2011, BioDrugs 25: 365-379). Critical to overcome the initial barrier of cytokine storm as described for catumaxomab (Berek et al. 2014, Int. J. Gynecol. Cancer 24(9): 1583-1589; Mau-Sorensen et al. 2015, Cancer Chemother. Pharmacol. 75: 1065-1073), was the absence or silencing of the Fc domain.
The CD20 molecule (also called human B-lymphocyte-restricted differentiation antigen or Bp35) is a hydrophobic transmembrane protein with a molecular weight of approximately 35 kD located on pre-B and mature B lymphocytes (Valentine et al. (1989) J. Biol. Chem. 264(19):11282-11287; and Einfield et al., (1988) EMBO J. 7(3):711-717). CD20 is found on the surface of greater than 90% of B cells from peripheral blood or lymphoid organs and is expressed during early pre-B cell development and remains until plasma cell differentiation. CD20 is present on both normal B cells as well as malignant B cells. In particular, CD20 is expressed on greater than 90% of B cell non-Hodgkin's lymphomas (NHL) (Anderson et al. (1984) Blood 63(6):1424-1433), but is not found on hematopoietic stem cells, pro-B cells, normal plasma cells, or other normal tissues (Tedder et al. (1985) J. Immunol. 135(2):973-979).
Methods for treating cancer as well as autoimmune and immune diseases by targeting CD20 are known in the art. For example, the chimeric CD20 antibody rituximab has been used for or suggested for use in treating cancers such as non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). The human monoclonal CD20 antibody ofatumumab has been used for or suggested for use in treating among others various CLL indications, follicular lymphoma (FL), neuromyelitis optica (NMO), diffuse and relapsing-remitting multiple sclerosis (RRMS). The human monoclonal CD20 antibody obinutuzumab has been used for or suggested for use in treating CLL. Furthermore, the humanized CD20 antibody ocrelizumab is being developed for RRMS.
Gall et al. (2005 Experimental Hematology 33: 452) disclose the CD3×CD20 bispecific antibody CD20bi resulting from the chemical heteroconjugation of the CD20-specific chimeric antibody Rituximab (Rituxan) to anti-CD3 (Orthoclone OKT-3).
Stanglmaier et al. (2008 Int. J. Cancer: 123, 1181) describe the trifunctional bispecific anti-CD3×anti-CD20 antibody Bi20/FBTA05 combining a CD20-specific mouse IgG2a and a CD3-specific rat IgG2b.
Wu et al. (2007 Nat Biotechnol. 25: 1290-1297) and WO2011014659 describe a dual-specific (CD3 and CD20), tetravalent immunoglobulin G (dual-variable-domain immunoglobulin, DVD-Ig).
WO2011090762 describes the generation of a CD3×CD20 polypeptide heterodimer.
WO2011028952 describes amongst others the generation of CD3×CD20 bispecific molecules using Xencor's XmAb bispecific Fc domain technology.
WO2014047231 describes REGN1979 and other CD3×CD20 bispecific antibodies generated using the FcAAdp technology from Regeneron Pharmaceuticals.
Sun et al. (2015, Science Translational Medicine 7, 287ra70) describe a B cell-targeting anti-CD20/CD3 T cell-dependent bispecific antibody constructed using “knobs-into-holes” technology.
Bispecific antibodies that bind to both CD3 and CD20 may be useful in therapeutic settings in which specific targeting and T cell-mediated killing of cells that express CD20 is desired, and there is still a need for further efficient CD3×CD20 bispecific antibodies.